Acknowledgments to reviewers of World Journal of Clinical Oncology

INTRODUCTION
Cutaneous malignant melanoma represents the major
cause of mortality among skin cancers and its incidence
rate is increasing during last years [1-5] . Although the localized
cutaneous melanomas diagnosed in the early stages
are usually curable by surgical resection of malignant
tumors, the rapid progression to invasive and metastatic
disease states is generally associated with a poor median
survival of 6 mo to 12 mo and a five year survival rate
of less than 10% [1,2,6-8] . The therapeutic options for the
patients with unresectable melanomas and metastases at
distant organs such as lungs, liver and brain consisting
to the radiation therapy and/or chemotherapy are only
palliative, aiming to improve the quality of life of patients
[8-10] . Especially, the standard treatment with alkylating
agent, dacarbazine or its orally active analog temozolomide,
alone or in combination with other cytotoxic
agents, is ineffective in the most cases and culminate to
the development of drug resistance, disease relapse and
the death of melanoma patients [11-13] .
Importantly, recent advances in melanoma research
have led to the establishment of the molecular oncogenic
events that may contribute to melanoma initiation
and progression and treatment resistance of melanoma
cells. It has been observed that the persistent activation
of different oncogenic signaling cascades initiated in an
autocrine or a paracrine manner by distinct growth factors
and cytokines through their cognate receptors is
typically involved in the sustained proliferation, survival,
invasion and metastases at near lymph nodes and distant
sites of melanoma cells and angiogenic process [2,14-23] .
These deregulated gene products include B-Raf V600E ,
N-Ras Q61R , epidermal growth factor receptor (EGFR),
hepatocyte growth factor (HGF) receptor MET, plateletderived
growth factor receptors (PDGFRs), sonic hedgehog,
Wnt/β-catenin, Notch, Nodal/Cripto, hyaluronan
(HA)/CD44, stem cell-factor (SCF) receptor KIT,
stromal cell-derived factor-1 (SDF-1)/CXC chemokine
receptor-4 (CXCR4), and vascular endothelial growth
factor (VEGF)/VEGFR receptor (Figure 1) [13,14,17,19,22,24-47] .
These tumorigenic pathways can cooperate for the sustained
activation of downstream signaling effectors such
as mitogen-activated protein kinases (MAPKs), phosphatidylinositol
3’-kinase (PI3K)/Akt, nuclear factor-kappaB
(NF-κB) and hypoxia-inducible factors (HIFs) for the
acquisition of a more malignant behavior by melanoma
cells during disease progression to locally advanced and
metastatic states.
In addition, recent advances in skin stem/progenitor
cell research have led to the identification of melanoma
cells endowed with stem cell-like properties and which
can provide critical functions for tumor growth, metastases
at distant sites, treatment resistance and disease relapse
[17,18,20,21,23,48,49] . More specifically, highly tumorigenic
melanoma stem/progenitor cells have been identified
in situ and isolated from primary and secondary melanoma
tumors, circulating melanoma cells and established
melanoma cell lines [20,21,50-64] . Melanoma stem/progenitor
WJCO|www.wjgnet.com
Mimeault M et al . Novel biomarkers and targets in melanomas
cells may express different stem cell-like markers such
as CD133, nestin, aldehyde dehydrogenase (ALDHhigh
), CD166, neural crest nerve growth factor receptor
(CD271) and/or ATP-binding cassette (ABC) multidrug
resistance transporters such as multidrug resistance-1
encoding P-glycoprotein (P-gp), ABCG2 and ABCB5.
It has been shown that highly tumorigenic melanoma
stem/progenitor cells can give arise to the total tumor
cell mass in vivo with the phenotypic features resembling
to original patient’s melanomas and metastasize at distant
sites [50-58,60,61,63-65] . In this matter, we review the most
recent advancements on the gene products that are often
altered during melanoma initiation and progression to
locally invasive and metastatic disease states and which
may be exploited to develop novel multiplex biomarker
detection methods for optimizing diagnosis and prognosis
and multitargeted therapies for a more effective management
of melanoma patients.
NEW BIOMARKERS FOR OPTIMIZING DI-
AGNOSIS, PROGNOSIS AND INDIVIDU-
ALIZED TREATMENT OF MELANOMA
PATIENTS
The clinical diagnosis of cutaneous malignant melanomas
at early stages retains a big challenge for the experimented
pathologists and is generally made only after they
become visible on skin [66] . Moreover, a skin biopsy and
different tumor imaging tests such as X-rays, computed
tomography (CT) scan, magnetic resonance imaging
(MRI) and positron emission tomography (PET) tests
are often performed to establish the grades and stages of
melanomas and screen for metastatic melanomas [66,67] .
In addition, the immunohistochemical staining of
tissue specimens with different antibodies directed
against different melanocytic markers such as S-100
and melanoma-associated antigen recognized by T-cells
(MART-1) also designated as melanocyte antigen
(Melan-A), which is expressed by melanoma cells, is
useful for improving the accuracy of the pathological
diagnosis and prognosis of melanoma patients [68-70] .
Moreover, monoclonal antibody gp100 corresponding
to clone HMB-45, which is highly specific and sensitive
for melanocytic tumors but does not react with other
non-melanoma malignancies such as carcinomas,
lymphomas and sarcomas and normal melanocytes, may
be used for the pathological diagnosis to distinguish
poorly differentiated melanoma subtypes of other tumor
types [69,71] . The immunohistochemical analysis of the vimentin
expression in primary melanoma tissues, which is
frequently overexpressed in primary melanoma patients
with hematogenous metastasis, also may help to establish
the melanoma patients with a high risk to develop
hematogenous metastasis [72] . Although this importance
advance, few biomarkers in melanoma stem/progenitor
cells and their progenies have been validated in the clinics
to use in combination in screening methods for an early
33 March 10, 2012|Volume 3|Issue 3|